Elevations of neutrophil-to-lymphocyte ratio and C-reactive protein over time as a precursor to anaplastic transformation of papillary thyroid carcinoma: a case report

Background Papillary thyroid carcinoma rarely undergoes anaplastic transformation. Some risk factors for anaplastic transformation of thyroid cancer are known, but such transformation is difficult to predict in practice. We report a case demonstrating elevations of neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) over time as a precursor to anaplastic transformation of thyroid carcinoma. Case presentation The patient was an 89 year-old woman with a history of chronic aortic dissection. She was referred to our department after her local doctor detected thyroid nodules. She had previously been found to have multinodular goiter and enlarged left cervical lymph nodes on computed tomography. Her chief complaint was cervical discomfort and hoarseness. Blood tests revealed: white blood cells (WBCs), 4900 /µL; CRP, 0.29 mg/dL; neutrophils, 64.4%; and lymphocytes, 25.4%. A 21 mm mass was identified in the upper left lobe. Left III (16 mm) and left VI (16 mm) lymph node were enlarged on ultrasonography. Fine-needle aspiration cytology diagnosed malignant papillary carcinoma. However, due to the advanced age and medical history of the patient, a non-surgical policy was implemented. The primary tumor grew to 4 cm in diameter by 9 months after diagnosis, and blood tests showed: WBC, 7700 /µL; CRP, 0.18 mg/dL; neutrophils, 65.3%; and lymphocytes, 22.3%. By 10 months after diagnosis, the tumor had increased rapidly in diameter to 8 cm, with blood tests showing: WBC, 6500 /µL; CRP, 1.01 mg/dL; neutrophils, 68.2%; and lymphocytes, 19.3%. Anaplastic transformation of papillary thyroid carcinoma was diagnosed, and the patient was placed on treatment under a policy of best supportive care. Multiple lung metastases appeared 11 months after diagnosis, and blood test results showed: WBC, 13,300 /μL; CRP, 11.28 mg/dL; neutrophils, 93.6%; and lymphocytes, 2.3%. Unfortunately, the patient died of disease progression 63 days after identification of undifferentiated metastasis. Conclusions Chances to see the natural history of anaplastic transformation of thyroid cancer are rare. Elevations in NLR and CRP over time may be precursors to anaplastic transformation.


Background
Anaplastic thyroid carcinoma (ATC) shows an unfortunate course due to rapid disease progression.Clinical manifestations include rapidly enlarging cervical tumor, neck pain, hoarseness, dysphagia, and dyspnea.Imaging findings include invasion of surrounding organs and lymph node metastasis from the neck to the mediastinum.Blood test findings include a mildly elevated white blood cell (WBC) count, elevated C-reactive protein (CRP), and elevated sedimentation rate.
Anaplastic transformation (AT) of thyroid carcinoma is a rare occurrence.Risk factors for AT of thyroid carcinoma include the presence of highly differentiated carcinoma [1], advanced age, and long-term multinodular goiter [2].In recent years, genes related to the development and progression of thyroid cancer have been identified, and telomerase reverse transcriptase promoter mutations in papillary thyroid carcinoma (PTC) have been identified as a risk factor for AT [3].However, AT of thyroid cancer in advance remains challenging.We describe herein a case in which the natural history of AT in PTC could be observed and the neutrophil-to-lymphocyte ratio (NLR) and CRP level increased over time.
Fine-needle aspiration cytology (FNAC) showed papillary aggregates of follicular cells and intranuclear cytoplasmic inclusion bodies and confirmed malignancy from the primary tumor and cervical lymph nodes, leading to a diagnosis of PTC (Fig. 2).A review of previous imaging studies revealed multinodular goiter on computed tomography (CT) 11 years earlier (Fig. 3A), papillary carcinoma evident 6 years earlier (Fig. 3B), and metastasis in the left VI lymph node 5 years earlier (Fig. 3C).PTC cT3bN1bM0 was diagnosed, but due to the advanced age of the patient, the history of chronic arterial dissection, and the poor performance status, nonoperative management with close follow-up was chosen.

Discussion
ATC can be suspected based on clinical symptoms, imaging findings, and blood test results.
Leukocytosis and high levels of CRP cases should be considered infectious complications such as cervical abscess and pneumonia.Some ATCs cause tumor necrosis but most cases are associated with extrathyroidal invasion, lymph node metastasis, and distant metastasis.Cervical abscesses often triggered by dental infections or tonsilitis and may spread to the mediastinum.However, this case had no preceding infection and no obvious signs of abscess formation.Also, while large thyroid tumors can cause aspiration pneumonia, there were no signs of pneumonia on the CT when multiple lung metastases and pleural effusion were observed.
The most strongly suspected clinical diagnosis was AT of PTC.Unfortunately, no FNAC or biopsy was performed, so the pathology could not be confirmed.for ATC [4,5].Iwasaki et al. reported three cases of AT during lenvatinib treatment for differentiated thyroid cancer and recommended monitoring the clinical course and leukocyte count [6].The present case was preceded by leukocytosis and increase over time in NLR and CRP levels.Inflammatory markers include NLR, LMR, and PLR, which are prognostic factors for various cancers.NLR is considered useful in differentiating between PTC, poorly differentiated thyroid carcinoma (PDTC), and ATC, with a cutoff of 3.8 between PDTC and ATC [7].A meta-analysis suggested that pretreatment NLR in thyroid cancer may serve as a biomarker for predicting tumor growth, metastasis, and prognosis [8].In addition, a group with elevated NLR during the disease course exhibited poorer prognosis compared to a group without elevated NLR [9].Ahn et al. reported that a low LMR is associated with lower survival in patients with ATC [10].However, Yamazaki et al. found no significant difference in OS associated with LMR in their study [9,11].Furthermore, PLR did not show any association with OS in ATCs [9,11].
The combination of platelet counts and neutrophil to lymphocyte ratio (COP-NLR) in gastric carcinoma [12], and PI based on WBC and CRP levels in non-small cell lung carcinoma (NSCLC) [13] are used as inflammatory markers.In this case, COP-NLR1 was observed after AT, indicating an increase in NLR without a rise in platelet count, reflecting the elevated NLR.Additionally, PI for NSCLC showed PI 2 at the time of advanced stage with distant metastasis, making prediction of AT challenging.Both markers require further research to confirm their prognostic roles in ATC.
No previous reports have described serial NLRs over time during follow-up in a case resulting in AT.Elevated NLR may help in noticing AT in thyroid cancer.

Conclusion
Chances to see the natural history of AT of PTC are rare.This case showed elevated NLR and CRP as a precursor to AT.

Fig. 1 Fig. 2
Fig. 1 US findings in the neck.There is a 21 × 17 × 13 mm hypoechoic mass in the upper left lobe with an irregular shape and microcalcifications.Invasion of the sternal thyroid muscle is evident, along with enlargement of the left III and left VI lymph nodes

Fig. 3
Fig. 3 Review of previous CT findings.A Multiple thyroid nodules are seen within the thyroid gland.B Appearance of primary papillary thyroid carcinoma.C Appearance of left VI lymph node metastasis

Fig. 4
Fig. 4 Anaplastic transformation and blood test findings.This figure shows changes in blood tests during the course of anaplastic transformation of papillary thyroid carcinoma.From X + 8 months, tumor growth and decreasing lymphocyte ratio are observed.At X + 10 months, rapid tumor growth, increased NLR, and elevated CRP are observed.At X + 11 months, multiple lung metastases appear, and WBC, NLR, and CRP are all abnormally high